In July 2017, the AML Global Portal (AGP) reported on published data from the phase I/II dose-escalation Chrysalis study, which demonstrated that single agent gilteritinib, a potent, oral Fms-like Tyrosine Kinase 3 (FLT3)/AXL inhibitor, had a favorable safety profile and was effective in patients with relapsed/refractory Acute Myeloid Leukemia (AML) with FLT3 mutations. More results from this study are reported here.1
Keith Pratz, MD, from the John Hopkins University, Baltimore, presented at the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, preliminary data from the phase I dose-escalation/expansion study (NCT02236013), which evaluated the safety and anti-tumor activity of gilteritinib in combination with intensive chemotherapy in adult patients with newly diagnosed AML with or without FLT3 mutations.2
As of October 2017, 50 AML patients with a median age of 59 years (range, 23–77 years) were enrolled in this study. FLT3 mutation status was available for 48 patients; 47.9% (23/48) were positive for FLT3 mutation (FLT3mut+) and 52% (25/48) were negative (FLT3mut-).
Dose-escalation of gilteritinib occurred sequentially and patients (n = 17) were administered one of three dose-levels oral of gilteritinib of either 40, 80, or 120 mg/day on Days 1–14 or 4–7 (due to DLTs) of induction therapy. During induction, patients were administered up to two cycles of cytarabine (100 mg/m2/day, Days 1–7) and idarubicin (12 mg/m2/day, Days 1–3). During consolidation, patients were administered cytarabine (1.5 g/m2 every 12 hours, Days 1, 3, and 5) and once-daily gilteritinib (Days 1–14) at the induction dose for up to three cycles.Patients in the expansion cohort (n = 33) of this study were administered gilteritinib at the recommended dose +-+established at the dose-escalation stage of the study.
The primary endpoints of the study were safety and Maximum Tolerated Dose (MTD) of gilteritinib when combined with 7+3 induction and high-dose cytarabine (HiDAC) consolidation.
Key findings in patients (n = 44) evaluable for response:
- Dose Limiting Toxicities (DLTs) of prolonged neutropenia/ thrombocytopenia and decreased ejection fraction occurred in two patients respectively in the 40 mg/day cohort
- MTD: not reached
- Recommended expansion dose: 120 mg/day gilteritinib
- Grade ≥ 3 treatment-related Adverse Effects (AEs) occurred in ≥ 10% of patients including febrile neutropenia (36.7%), thrombocytopenia (18.4%), neutropenia (16.3%), decreased platelet count (12.2%), sepsis (10.2%) and decreased white blood cell count (10.2%)
- Serious treatment-emergent AEs related to gilteritinib occurring in > 1 patient were febrile neutropenia (n = 8), sepsis (n = 2), small intestinal obstruction (n = 2), lung infection (n = 2) and decreased ejection fraction (n = 2)
- There were no deaths from the treatment-emergent AEs
- Composite Complete Remission (CRc) rate in FLT3mut+ (n = 21) and FLT3mut- (n = 23) patients: 100 % vs 60.9% respectively
- Median OS and duration of response: not reached
In an interview with the AGP, Keith Pratz noted that the responses observed in patients treated in this phase I trial has been “good so far”. He further concluded that in patients with newly diagnosed AML, gilteritinib in combination with intensive chemotherapy was “well tolerated” with an MTD at ≥ 120 mg/day. Additionally, a higher response for this combination regimen was seen in FLT3mut+ AML patients.
Keith Pratz added that although gilteritinib at doses of 120 mg /day was potent, it was not as robust as that observed with the same dose administered as monotherapy. Evaluation of a dose-escalation cohort of 200 mg/day gilteritinib is ongoing.